tbuckley/cabot-search huggingface dataset:
Human T-bet governs the generation of a distinct subset of CD11c <sup>high</sup> CD21 <sup>low</sup> B cells
Authors: Rui Yang, Danielle T. Avery, Katherine J. L. Jackson, Masato Ogishi, Ibtihal Benhsaien, Likun Du, Xiaofei Ye, Jing Han, Jérémie Rosain, Jessica N. Peel, Marie-Alexandra Alyanakian, Bénédicte Neven, Sarah Winter, Anne Puel, Bertrand Boisson, Kathryn J. Payne, Melanie Wong, Amanda J. Russell, Yoko Mizoguchi, Satoshi Okada, Gulbu Uzel, Christopher C. Goodnow, Sylvain Latour, Jalila El Bakkouri, Aziz Bousfiha, Kahn Preece, Paul E. Gray, Baerbel Keller, Klaus Warnatz, Stéphanie Boisson-Dupuis, Laurent Abel, Qiang Pan-Hammarström, Jacinta Bustamante, Cindy S. Ma, Jean-Laurent Casanova, Stuart G. Tangye
Journal: Science Immunology (2022)

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet–deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21 lo CD11c hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS , IL21R , SEC61B , DUSP4 , DAPP1 , SOX5 , CD79B , and CXCR4 . Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c hi CD21 lo B cells.
CXCL9 and CXCL10 bring the heat to tumors
Authors: Robin Reschke, Thomas F. Gajewski
Journal: Science Immunology (2022)

CXCL9 and CXCL10 can be produced by antigen-presenting cells (dendritic cells or macrophages) and by tumor cells. Hoch et al. demonstrated that CXCL9 and CXCL10 co-localize with LAG3 + T cells expressing CCL4 or CXCL13 and contribute to the generation of a “hot” tumor microenvironment.
TREM2 macrophages induced by human lipids drive inflammation in acne lesions
Authors: Tran H. Do, Feiyang Ma, Priscila R. Andrade, Rosane Teles, Bruno J. de Andrade Silva, Chanyue Hu, Alejandro Espinoza, Jer-En Hsu, Chun-Seok Cho, Myungjin Kim, Jingyue Xi, Xianying Xing, Olesya Plazyo, Lam C. Tsoi, Carol Cheng, Jenny Kim, Bryan D. Bryson, Alan M. O’Neill, Marco Colonna, Johann E. Gudjonsson, Eynav Klechevsky, Jun Hee Lee, Richard L. Gallo, Barry R. Bloom, Matteo Pellegrini, Robert L. Modlin
Journal: Science Immunology (2022)

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.
Safety and efficacy of istaroxime in patients with acute heart failure‐related pre‐cardiogenic shock – a multicentre, randomized, double‐blind, placebo‐controlled, parallel group study (<scp>SEISMiC</scp>)
Authors: Marco Metra, Ovidiu Chioncel, Gad Cotter, Beth Davison, Gerasimos Filippatos, Alexandre Mebazaa, Maria Novosadova, Piotr Ponikowski, Phillip Simmons, Joseph Soffer, Steven Simonson
Journal: European Journal of Heart Failure (2022)
Immunogenicity induced by two and three doses of the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases and immunocompetent controls: a longitudinal multicentre study
Authors: Victoria Furer, Tali Eviatar, Tal Freund, Hagit Peleg, Daphna Paran, David Levartovsky, Ilana Kaufman, Adi Broyde, Ofir Elalouf, Ari Polachek, Joy Feld, Amir Haddad, Tal Gazitt, Muna Elias, Nizar Higazi, Fadi Kharouf, Smadar Gertel, Sara Pel, Sharon Nevo, David Hagin, Devy Zisman, Ori Elkayam
Journal: Annals of the Rheumatic Diseases (2022)

To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls.A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample.The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1.The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients.
A clade C HIV-1 vaccine protects against heterologous SHIV infection by modulating IgG glycosylation and T helper response in macaques
Authors: Anusmita Sahoo, Andrew T. Jones, Narayanaiah Cheedarla, Sailaja Gangadhara, Vicky Roy, Tiffany M. Styles, Ayalnesh Shiferaw, Korey L. Walter, LaTonya D. Williams, Xiaoying Shen, Gabriel Ozorowski, Wen-Hsin Lee, Samantha Burton, Lasanajak Yi, Xuezheng Song, Zhaohui S. Qin, Cynthia A. Derdeyn, Andrew B. Ward, John D. Clements, Raghavan Varadarajan, Georgia D. Tomaras, Pamela A. Kozlowski, Galit Alter, Rama Rao Amara
Journal: Science Immunology (2022)

The rising global HIV-1 burden urgently requires vaccines capable of providing heterologous protection. Here, we developed a clade C HIV-1 vaccine consisting of priming with modified vaccinia Ankara (MVA) and boosting with cyclically permuted trimeric gp120 (CycP-gp120) protein, delivered either orally using a needle-free injector or through parenteral injection. We tested protective efficacy of the vaccine against intrarectal challenges with a pathogenic heterologous clade C SHIV infection in rhesus macaques. Both routes of vaccination induced a strong envelope-specific IgG in serum and rectal secretions directed against V1V2 scaffolds from a global panel of viruses with polyfunctional activities. Envelope-specific IgG showed lower fucosylation compared with total IgG at baseline, and most of the vaccine-induced proliferating blood CD4+ T cells did not express CCR5 and α4β7, markers associated with HIV target cells. After SHIV challenge, both routes of vaccination conferred significant and equivalent protection, with 40% of animals remaining uninfected at the end of six weekly repeated challenges with an estimated efficacy of 68% per exposure. Induction of envelope-specific IgG correlated positively with G1FB glycosylation, and G2S2F glycosylation correlated negatively with protection. Vaccine-induced TNF-α+ IFN-γ+ CD8+ T cells and TNF-α+ CD4+ T cells expressing low levels of CCR5 in the rectum at prechallenge were associated with decreased risk of SHIV acquisition. These results demonstrate that the clade C MVA/CycP-gp120 vaccine provides heterologous protection against a tier2 SHIV rectal challenge by inducing a polyfunctional antibody response with distinct Fc glycosylation profile, as well as cytotoxic CD8 T cell response and CCR5-negative T helper response in the rectum.
Accelerating cardiovascular research: recent advances in translational <scp>2D</scp> and <scp>3D</scp> heart models
Authors: Elisa Mohr, Thomas Thum, Christian Bär
Journal: European Journal of Heart Failure (2022)

In vitro modelling the complex (patho-) physiological conditions of the heart is a major challenge in cardiovascular research. In recent years, methods based on three-dimensional (3D) cultivation approaches have steadily evolved to overcome the major limitations of conventional adherent two-dimensional (2D) monolayer cultivation. These 3D approaches aim to study, reproduce or modify fundamental native features of the heart such as tissue organization and cardiovascular microenvironment. Therefore, these systems have great potential for (patient-specific) disease research, for the development of new drug screening platforms, and for the use in regenerative and replacement therapy applications. Consequently, continuous improvement and adaptation is required with respect to fundamental limitations such as cardiomyocyte maturation, scalability, heterogeneity, vascularization, and reproduction of native properties. In this review, 2D monolayer culturing and the 3D in vitro systems of cardiac spheroids, organoids, engineered cardiac microtissue and bioprinting as well as the ex vivo technique of myocardial slicing are introduced with their basic concepts, advantages, and limitations. Furthermore, recent advances of various new approaches aiming to extend as well as to optimize these in vitro and ex vivo systems are presented.
Effects of steroidal mineralocorticoid receptor antagonists on acute and chronic estimated glomerular filtration rate slopes in patients with chronic heart failure
Authors: Muthiah Vaduganathan, João Pedro Ferreira, Patrick Rossignol, Brendon L. Neuen, Brian L. Claggett, Marc A. Pfeffer, John J.V. McMurray, Bertram Pitt, Faiez Zannad, Scott D. Solomon
Journal: European Journal of Heart Failure (2022)
Jessel Josephs
Authors: David Josephs
Journal: BMJ (2022)

<h3>ABSTRACT</h3> ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we used a viral-like particle trapping technology to identify ISG15-binding proteins and discovered Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly-characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We found that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We showed that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1 (HSV-1), human respiratory syncytial virus (RSV) and coxsackievirus B3 (CVB3), and we observed a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide novel molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
When I use a word . . . . Too much healthcare—too much of everything
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) have shorter life expectancy and their risk of cardiovascular (CV) death is more than 50% higher than the rest of the population. Early myocardial dysfunction may be detectable more precisely and sooner using speckle tracking echocardiography. <h3>Objectives</h3> This study was designed to assess myocardial (LV) systolic function by STE (speckletracking Echocardiography) strain imaging in patients with RA without known CVD and to correlate the findings with characters of the disease. <h3>Methods</h3> Cross-sectional observational study enrolled 60 patients with RA (mean age 46.22 ± 8.14 years) without known CVD, and 20 healthy controls. All subjects underwent a standard echocardiographic examination as well as the speckle tracking assessment of left ventricle strains. <h3>Results</h3> Speckle-tracking assessment of LV systolic function revealed decreased GLS among the patients group (-16.80% vs. -22.35%, P&lt;0.001). There was a negative correlation between the duration of RA and the GLS (r = - 0.301). Receiver operating characteristics (ROC) curve was used to define the best cut off value of GLS which was -20, with sensitivity of 76.7%, specificity of 80%, positive predictive value of 92%, negative predictive value of 63% with diagnostic accuracy of 83.9%. <h3>Conclusion</h3> The speckletracking method for myocardial strain analysis showed unambiguously systolic impairment of longitudinal strain parameters. So, patients with RA should undergo a full comprehensive echocardiographic study for assessment of LV systolic function. <h3>References</h3> [1] SHARMA A, KAUSHIK R, KAUSHIK RM, KAKKAR R: Echocardiographic evaluation of diastolic dysfunction in rheumatoid arthritis– a case–control study. Mod Rheumatol 25: 552- 557, 2015. [2] KARPOUZAS GA, MALPESO J, CHOI TY, LI D, MUNOZ S, et al.: Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 73: 1797-1804, 2014. <h3>Disclosure of Interests</h3> None declared
Cardiomyocyte-Specific Long Noncoding RNA Regulates Alternative Splicing of the Triadin Gene in the Heart
Authors: Yuanbiao Zhao, Andrew S. Riching, Walter E. Knight, Congwu Chi, Lindsey J. Broadwell, Yanmei Du, Mostafa Abdel-Hafiz, Amrut V. Ambardekar, David C. Irwin, Catherine Proenza, Hongyan Xu, Leslie A. Leinwand, Lori A. Walker, Kathleen C. Woulfe, Michael R. Bristow, Peter M. Buttrick, Kunhua Song
Journal: Circulation (2022)

Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive.We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart.We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA.These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.
Creation of the American Heart Association Journals’ Equity, Diversity, and Inclusion Editorial Board: The Next Step to Achieving the 2024 Impact Goal
Authors: Eldrin F. Lewis, Christine Beaty, Johannes Boltze, Khadijah Breathett, Walter K. Clair, Lisa de las Fuentes, Utibe R. Essien, Heather Goodell, H.E. Hinson, Kiarri N. Kershaw, Joshua W. Knowles, Sula Mazimba, Mahasin Mujahid, Henry E. Okafor, Kyung Woo Park, Jonathan Schultz
Journal: Circulation (2022)
Effect of Patient-Reported Preprocedural Physical and Mental Health on 10-Year Mortality After Percutaneous or Surgical Coronary Revascularization
Authors: Masafumi Ono, Patrick W. Serruys, Scot Garg, Hideyuki Kawashima, Chao Gao, Hironori Hara, Mattia Lunardi, Rutao Wang, Neil O’Leary, Joanna J. Wykrzykowska, Jan J. Piek, Michael J. Mack, David R. Holmes, Marie-Claude Morice, Arie Pieter Kappetein, Daniel J.F.M. Thuijs, Thilo Noack, Friedrich W. Mohr, Piroze M. Davierwala, John A. Spertus, David J. Cohen, Yoshinobu Onuma
Journal: Circulation (2022)

Clinical and anatomical characteristics are often considered key factors in deciding between percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with complex coronary artery disease (CAD) such as left-main CAD or 3-vessel disease. However, little is known about the interaction between self-reported preprocedural physical/mental health and clinical outcomes after revascularization.This subgroup analysis of the SYNTAXES trial (SYNTAX Extended Survival), which is the extended follow-up of the randomized SYNTAX trial (Synergy Between PCI With Taxus and Cardiac Surgery) comparing PCI with CABG in patients with left-main CAD or 3-vessel disease, stratified patients by terciles of Physical (PCS) or Mental Component Summary (MCS) scores derived from the preprocedural 36-Item Short Form Health Survey, with higher PCS and MCS scores representing better physical and mental health, respectively. The primary end point was all-cause death at 10 years.A total of 1656 patients with preprocedural 36-Item Short Form Health Survey data were included in the present study. Both higher PCS and MCS were independently associated with lower 10-year mortality (10-point increase in PCS adjusted hazard ratio, 0.84 [95% CI, 0.73-0.97]; P=0.021; in MCS adjusted hazard ratio, 0.85 [95% CI, 0.76-0.95]; P=0.005). A significant survival benefit with CABG over PCI was observed in the highest PCS (>45.5) and MCS (>52.3) terciles with significant treatment-by-subgroup interactions (PCS Pinteraction=0.033, MCS Pinteraction=0.015). In patients with both high PCS (>45.5) and MCS (>52.3), 10-year mortality was significantly higher with PCI compared with CABG (30.5% versus 12.2%; hazard ratio, 2.87 [95% CI, 1.55-5.30]; P=0.001), whereas among those with low PCS (≤45.5) or low MCS (≤52.3), there were no significant differences in 10-year mortality between PCI and CABG, resulting in a significant treatment-by-subgroup interaction (Pinteraction=0.002).Among patients with left-main CAD or 3-vessel disease, patient-reported preprocedural physical and mental health status was strongly associated with long-term mortality and modified the relative treatment effects of PCI versus CABG. Patients with the best physical and mental health had better 10-year survival with CABG compared with PCI. Assessment of self-reported physical and mental health is important when selecting the optimal revascularization strategy.URL: https://www.gov; SYNTAXES Unique identifier: NCT03417050. URL: https://www.gov; SYNTAX Unique identifier: NCT00114972.
Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction
Authors: Sebastian Rosch, Karl-Patrik Kresoja, Christian Besler, Karl Fengler, Anne Rebecca Schöber, Maximilian von Roeder, Christian Lücke, Matthias Gutberlet, Karin Klingel, Holger Thiele, Karl-Philipp Rommel, Philipp Lurz
Journal: Circulation (2022)

Background: Recent trial data suggest that stratification of patients with heart failure with preserved ejection fraction (HFpEF) according to left ventricular ejection fraction (LVEF) provides a means for dissecting different treatment responses. However, the differential pathophysiologic considerations have rarely been described. Methods: This prospective, single-center study analyzed consecutive symptomatic patients with HFpEF diagnosed according to the 2016 European Society of Cardiology heart failure guidelines. Patients were grouped into LVEF 50% to 60% and LVEF &gt;60% cohorts. All patients underwent cardiac magnetic resonance imaging. Transfemoral cardiac catheterization was performed to derive load-dependent and load-independent left ventricular (LV) properties on pressure–volume loop analyses. Results: Fifty-six patients with HFpEF were enrolled and divided into LVEF 50% to 60% (n=21) and LVEF &gt;60% (n=35) cohorts. On cardiac magnetic resonance imaging, the LVEF &gt;60% cohort showed lower LV end-diastolic volumes ( P =0.019) and end-systolic volumes ( P =0.001) than the LVEF 50% to 60% cohort; stroke volume ( P =0.821) did not differ between the cohorts. Extracellular volume fraction was higher in the LVEF 50% to 60% cohort than in the LVEF &gt;60% cohort (0.332 versus 0.309; P =0.018). Pressure-volume loop analyses demonstrated higher baseline LV contractility (end-systolic elastance, 1.85 vs 1.33 mm Hg/mL; P &lt;0.001) and passive diastolic stiffness (β constant, 0.032 versus 0.018; P =0.004) in the LVEF &gt;60% cohort. Ventriculo-arterial coupling (end-systolic elastance/arterial elastance) at rest was in the range of optimized stroke work in the LVEF &gt;60% cohort but was impaired in the LVEF 50% to 60% cohort (1.01 versus 0.80; P =0.005). During handgrip exercise, patients with LVEF &gt;60% had higher increases in end-systolic elastance (1.85 versus 0.82 mm Hg/mL; P =0.023), attenuated increases in indexed end-systolic volume (−1 versus 7 mL/m²; P &lt;0.004), and more exaggerated increases in LV filling pressures (8 vs 5 mm Hg; P =0.023). LV stroke volume decreased in the LVEF &gt;60% cohort ( P =0.007) under exertion. Conclusions: Patients with HFpEF in whom LVEF ranged from 50% to 60% demonstrated reduced contractility, impaired ventriculo-arterial coupling, and higher extracellular volume fraction. In contrast, patients with HFpEF and a LVEF &gt;60% demonstrated a hypercontractile state with excessive LV afterload and diminished preload reserve. A LVEF-based stratification of patients with HFpEF identified distinct morphologic and pathophysiologic subphenotypes.